Pharmacophore-Aided Virtual Screening and Molecular Dynamics Simulation Identifies TrkB Agonists for Treatment of CDKL5-Deficiency Disorders.

Therapeutic intervention in cyclin-dependent kinase-like 5 (CDKL5) deficiency disorders (CDDs) has remained a concern over the years. Recent advances into the mechanistic interplay of signalling pathways has revealed the role of deficient tropomyosin receptor kinase B (TrkB)/phospholipase C γ1 signalling cascade in CDD. Novel findings showed that in vivo administration of a TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), resulted in a remarkable reversal in the molecular pathologic mechanisms underlying CDD. Owing to this discovery, this study aimed to identify more potent TrkB agonists than 7,8-DHF that could serve as alternatives or combinatorial drugs towards effective management of CDD. Using pharmacophore modelling and multiple database screening, we identified 691 compounds with identical pharmacophore features with 7,8-DHF. Virtual screening of these ligands resulted in identification of at least 6 compounds with better binding affinities than 7,8-DHF. The in silico pharmacokinetic and ADMET studies of the compounds also indicated better drug-like qualities than those of 7,8-DHF. Postdocking analyses and molecular dynamics simulations of the best hits, 6-hydroxy-10-(2-oxo-1-azatricyclo[7.3.1.05,13]trideca-3,5(13),6,8-tetraen-3-yl)-8-oxa-13,14,16-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1,3,6,9,11,15-hexaen-5-one (PubChem: 91637738) and 6-hydroxy-10-(8-methyl-2-oxo-1H-quinolin-3-yl)-8-oxa-13,14,16-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1,3,6,9,11,15-hexaen-5-one (PubChem ID: 91641310), revealed unique ligand interactions, validating the docking findings. We hereby recommend experimental validation of the best hits in CDKL5 knock out models before consideration as drugs in CDD management.